Abstract 276: Angiotensin AT1 Receptor Blockade Reverses Age-Related Changes in Myocardial Energy Metabolism and Increases Mitochondrial Biogenesis

Abstract

Aging and mitochondrial function have been closely linked. We recently reported the identification of a mitochondrial angiotensin system. We hypothesized that angiotensin AT1 receptor blockade would increase energy production and mitochondrial biogenesis and reduce oxidative stress in aging hearts. We used Magnetic resonance spectroscopy to measure cardiac energy metabolism and function in young (20 wks old), aged (150 wks old) mice at baseline and after 4 weeks of losartan (50 mg/kg/day). For mitobiogenesis, qPCR was used to calculate CytB (mitochondrial gene)/GAPDH (nuclear gene) ratio and to measure mito-survival genes Sirt1, Sirt3, Nampt, and PGC-1α. Cardiomyocyte mitochondria from young, aged and treated mice were examined with electron microscopy. The expression of nitrotyrosine was quantified by immunohistochemistry. Older animals hearts (n=9) exhibited increase in LV mass (103±9 mg versus 120±8 mg, young (n=8) versus old (n=9), P<0.002). The mean cardiac PCr/ATP was reduced in older animals (1.5±0.2) than that of young mice (2.0±0.3, P<0.0004). Losartan abolished the LV mass increase in older animals (109±11 mg vs 101±7 mg, young versus old, P<0.1) and improved the impaired energy metabolism of the older hearts increasing the PCr/ATP ratios towards those observed in younger animals (1.94±0.01 vs 1.87±0.4, control versus old, P<0.7). Losartan increased EF in older animals (56±5% vs 63±5%, old versus old treated, P<0.01). Losartan increased mitobiogenesis in the hearts of treated young and old mice (3.8+2.5 folds, P<0.02 and 4.3+ 0.9 folds, P<0.0001). Mito-survival genes in the heart were not increased but PGC-1α was up-regulated by 2.8+1.6-fold, P<0.05 and 7+ 1.9-fold, P<0.001 in young and old treated mice. Electron micrograph analysis revealed that aging was associated with swollen cardiac mitochondria and disrupted cristae, which were reversed by Losartan. Losartan in older animals significantly reduced oxidative damage as evidenced by less Nitrotyrosine staining score in cardiomyocytes (2.5±0.5 vs. 1.3±0.4, old versus old treated, P<0.0009). Our results indicate that Losartan in aging increased mitobiogenesis, reduced oxidative stress, improved energy production and restored cardiac function to the healthy young adult level.